Synthesis of macrocyclic tetraamido-N ligands

Abstract

New synthetic methods for the preparation of macrocyclic amido-N donor ligands are provided. The primary method of the present invention involves in general only two synthetic steps. In the first step, an alpha or beta amino carboxylic acid is allowed to react with an optimal (approximately stoichiometric) amount of an activated malonate or oxalate derivative with mild heating. Upon completion of the double coupling reaction, hydrolysis of the reaction mixture yields a diamide containing intermediate (a macro linker). In the second step, stoichiometric amounts of a diamine, preferably an orthophenylene diamine, are added to the macro linker intermediate in the presence of a coupling agent and heat. This second double coupling reaction, is allowed to proceed for a period of time sufficient to produce a macrocyclic tetraamido compound. The substituent groups on the alpha or beta amino carboxylic acid, the malonate, and the aryl diamine may all be selectively varied so that the resulting tetraamido macrocycle can be tailored to specific desired end uses. The macrocyclic tetraamide ligand may then be complexed with a metal, such as a transition metal, and preferably the middle and later transition metals, to form a robust chelate complex suitable for catalyzing oxidation reactions.

What we claim is: 
     
       1. A method comprising: reacting stoichiometric amounts or more of an amino carboxylic acid or a protected/activated for thereof with an activated dervative selected from the group consisting of oxalates and malonates in the presence of a solvent and heat to produce an amide intermediate having the structure ##STR79##  wherein Y 1  represents zero, one or two carbon containing nodes for substitution, and Y 3  and Y 4  each represent one or two carbon containing nodes for substitution, each said node containing a C(R) or a C(R) 2  unit and each R substituent is the same or different from the remaining R substituents and is selected from the group consisting of alkyl, aryl, hydrogen, halogen, CH 2  CF 3 , CF 3  and combinations thereof, or together with a paired R substituent bound to the same carbon atom form a cyclopentyl or cyclohexyl ring.   
     
     
       2. The method of claim 1 wherein the amino carboxylic acid is selected from the group consisting of α and β amino acids. 
     
     
       3. The method recited in claim 1 wherein said amino carboxylic acid or said protected/activated form of an amino carboxylic acid has the formula ##STR80## wherein Y is C(R 3 )(R 4 ), C(R 5 )(R 6 )C(R 7 )(R 8 ), or ##STR81## and R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12  are the same or different, pairwise and cumulatively, and comprise hydrogen, ketones, aldehydes, carboxylic acids, hidden or protected/activated carboxylic acids, esters, ethers, oxazalones, anhydrides, acyl halides, nitriles, oxazalines, acyl oximes, amides, hidden or protected/activated amines, imines, imides, amides, azides, azo compounds, nitrilium ions, hydrazines, carbanates, enamines, n-oxides, isocyanates, isothiocyanates, nitro, sulfonyls, sulfates, phosphoryls, phosphates, phosphazos, silyl, siloxanes, alkyl, alkenyl, alkynyl, halo, aryl, CH 2  CF 3 , CF 3  and combinations thereof. 
     
     
       4. The method of claim 1 wherein the heat to form said and intermediate is at a temperature equal to or less than about 70° C. 
     
     
       5. The method of claim 1 wherein the amino carboxylic acid is an α spiro-cyclohexyl amino carboxylic acid and the solvent is added in multiple aliquots at periodic intervals to yield a bis-cyclohexyl intermediate and an oxazalone species. 
     
     
       6. The method of claim 5 further comprising the step of hydrolyzing the oxazalone species in the presence of solvent to the bis-cyclohexyl intermediate. 
     
     
       7. The method of claim 1 wherein the solvent is selected from the group consisting of solvents suitable for performing acylations and aprotic solvents. 
     
     
       8. The method of claim 1 wherein the malonate activated derivative is selected from the group consisting of unsubstituted, monosubstituted and disubstituted malonates. 
     
     
       9. The method of claim 1 wherein the malonate activated derivative has the structure ##STR82## and the oxalate activated derivative has the structure ##STR83## wherein X is hydroxy, halogen or protected/activated hydroxy and R 1  and R 2  are the same or different, and are comprised of substituents containing hydrogen, ketones, aldehydes, carboxylic acids, hidden or protected/activated carboxylic acids, esters, ethers, amines, hidden or protected/activated amines, imines, amides, nitro, sulphonyls, sulfates, phosphoryls, phosphates, silyl, siloxanes, alkyl, alkenyl, alkyl, halo, or aryl. 
     
     
       10. The method of claim 1 further comprising adding to the intermediate a diamine in the presence of solvent and a coupling agent, and heating the resulting mixture for a period of time sufficient to form macrocyclic tetraamido compounds. 
     
     
       11. The method of claim 10 wherein the diamine is added under anhydrous conditions. 
     
     
       12. The method of claim 10 wherein said diamine is selected from the group consisting of n,n+1 alkyl diamines and 1,2-aryl diamines, substituted n,n+2 alkyl diamines, substituted o-amino benzylamines and substituted 1,8-diamino napthalenes. 
     
     
       13. The method of claim 10 wherein the coupling agent is selected from the group consisting of a phosphorous halide compound and pivaloyl chloride. 
     
     
       14. The method of claim 10 wherein the diamines are selected from the group having the general structure ##STR84## wherein R 13  to R 38  are the same or different, pairwise and cumulatively, and comprise hydrogen, CF 3 , ketones, aldehydes, esters, ethers, amines, imines, arides, nitro, sulphonyls, sulfates, phosphoryls, phosphates, silyl, siloxanes, alkyl, heteroatom substituted alkyl, alkenyl, alkynyl, halo, aryl and protected/activated and hidden carboxylic acids and protected/activated and hidden amines. 
     
     
       15. The method of claim 14 wherein the R groups of C(R 3 )(R 4 ), C(R 5 )(R 6 ) or C(R 6 )(R 7 ) are fused together to form cyclopentyl or cyclohexyl rings. 
     
     
       16. The method of claim 10 further comprising complexing a transition metal to the N-donors of said macrocylic tetraamido compound. 
     
     
       17. The method of claim 16 wherein said transition metal is a group VIA, VIIA, VIII or IB transition metal. 
     
     
       18. The method of claim 16 wherein said complexing step further comprises: deprotonating the N-donors of the macrocyclic tetraamido compound by treatment with a base;   adding a metal ion; and,   oxidizing to produce a metal chelate complex having the structure: ##STR85##  wherein M is the metal; Z is N; L 1  is a ligand; and, Ch 1 , Ch 2 , Ch 3  and Ch 4  are oxidation resistant components which are the same or different and which form five- to six-membered rings in combination with the adjacent ZMZ atoms.   
     
     
       19. The method recited in claim 18 wherein the ligand, L 1 , is selected from the group consisting of halide ions, CN - , H 2  O, OH - , ROH, NH 3 , amines, carboxylate, phenoxide, pyridine, ether, sulfoxide, ketone, nitriles, isonitriles and carbonate. 
     
     
       20. The method recited in claim 18 wherein the oxidation step comprises exposure to air, oxygen, chlorine, bromine or benzoyl peroxide. 
     
     
       21. The method recited in claim 18 wherein the base is selected from the group consisting of lithium bis-trimethylsilamide, lithium diisopropyl amide, t-butyl lithium, n-buty lithium, phenyl lithium. 
     
     
       22. The method recited in claim 18 wherein the base is a noncoordiating organic soluble base. 
     
     
       23. The method of claim 18 further comprising combining the metal chelate complex with an oxygen atom transfer oxidant. 
     
     
       24. The method of claim 20 further comprising attaching a protecting group to the diamine before addition of the diamine to the intermediate. 
     
     
       25. The method of claim 4 further comprising (4) adding to the product of claim 24, THF, a base and a metal salt in the presence of oxygen to form a metallated amino pendant macrocyclic tetraamido compound in protected form; and   (5) removing the protecting group.   
     
     
       26. The method of claim 25 further comprising covalently attaching the amino pendant macrocyclic tetraamido compound to a support. 
     
     
       27. The method of claim 26 wherein the support is selected from the group consisting of polymers, sand and molecules/substrates having functional groups which form a covalent bond with said amino. 
     
     
       28. The method of claim 26 wherein the amino pendant metallated macrocyclic compound is attached to the support by reacylation of the pendant amino group with acryloyl chloride; and copolymerizing with an excess of acryloyl monomers to yield an acrylic polymer having a plurality of macrocyclic metallated complexes as side chains.